Cardiovascular disease is a growing complication of HIV. Although there is an increased incidence associated with the infection itself, it is further complicated by the antiviral therapy prescribed to treat the disease. The cornerstone of the HAART drug regimen for treating HIV are nucleoside analog reverse transcriptase inhibitors (NRTIs), which inhibit viral RNA-dependent DNA polymerases. However, these drugs are also recognized by host cell DNA polymerases including Polg, which is responsible for replicating the mitochondrial genome. As a result, the NRTIs inhibit mtDNA replication and biogenesis leading to mitochondrial depletion, which is manifested as a dose-limiting lactic acidosis and life-threatening cardiomyopathy. Although there is considerable evidence implicating mitochondrial depletion in the pathogenesis of NRTI toxicity, little is known regarding the bioenergetic characteristics responsible for the mitochondrial phenotype. The purpose of this investigation is identify which NRTIs induce mitochondrial cardiomyopathy in animal models at relevant doses and to fully characterize the mitochondrial bioenergetic deficits that underlie the metabolic disorder. We propose that the loss of coordinated expression of the nuclear and mitochondrial genomes leads to the assembly of poorly coupled electron transport chains, resulting in a loss of efficiency of oxidative phosphorylation accompanied by the catalytic liberation of highly reactive oxygen free radicals. Mitochondrial cardiomyopathy likely reflects both bioenergetic failure and increased oxidative damage owing to this interference with mitochondrial biogenesis. The results of this investigation will provide valuable insight into distinguishing which NRTIs are cardiotoxic and identifying the underlying mechanisms in the pathogenesis of cardiac injury. This information will be essential to predicting possible interactions between components of the HAART drug regimen and for developing reliable biomarkers and/or new treatment strategies designed to minimize the cardiomyopathy and thus improve the clinical success of HIV pharmacotherapy.